(1) Field of the Invention
The present invention relates to tissue treatments and sealants. In particular, the present invention relates to cyanoacrylate tissue adhesives.
(2) Description of Related Art
Several different techniques have been used for internal wound closure and tissue fixation such as sutures, tapes, staples, ligating clips, and adhesives. Adhesives are easy to apply and reduce physical pain as well as the patient's anxiety associated with suture needles.
For internal applications, absorbable materials are highly preferred. Absorption eliminates the foreign body response characteristic of all permanent synthetic implants, and eliminates the need for a second surgery for material removal. The most widely used absorbable materials for internal tissue fixation and wound closure are sutures formed of degradable poly alpha-hydroxy acids, for example, polyglactin 910 (VICRYL®, Johnson and Johnson). Adhesives are particularly attractive because of their ability for simple, rapid application and curing.
Alkyl cyanoacrylate monomers have been used as tissue adhesives for several decades. Cyanoacrylate tissue adhesives are liquid monomers and can polymerize quickly on contact with tissue surface creating a thin, flexible film. This polymer film creates a mechanical barrier, which maintains a natural healing environment. Short alkyl chain cyanoacrylates such as methyl-, ethyl-, and isopropylcyanoacrylates were used as tissue adhesives, but because of their rapid in vivo degradation, resulting in significant tissue toxicity and inflammation, they were replaced by longer-chain cyanoacrylates such as butyl- and octylcyanoacrylate. Octylcyanoacrylate has received FDA approval in 1998 and is marketed for skin wound closure after lacerations or incisions.
Cyanoacrylates offer a number of advantages, specifically as internal adhesives. Because their polymerization is initiated by functional groups found on biomolecules in tissue, their tissue bonding capability is greater than other types of adhesives. Cyanoacrylate adhesives also exhibit excellent bond strength and very rapid cure time. Cyanoacrylate esters with very short alkyl side chains (methyl and ethyl) are rapidly absorbed, but result in significant tissue toxicity. Cyanoacrylate esters with longer alkyl side chains exhibit reduced toxicity, but undergo extremely slow absorption.
In order to address this limitation, several methods have been developed to accelerate degradation of cyanoacrylate adhesives. One method involves the introduction of a second ester bond during synthesis, which increases the susceptibility to hydrolysis (U.S. Pat. No. 6,620,846 to Jonn, et al.). Another method pioneered by Shalaby in U.S. Pat. Nos. 6,299,631 and 6,669,940 is the use of alkoxycyanoacrylate esters, specifically 2-methoxypropylcyanoacrylate, in combination with plasticizers of low molecular weight liquid polyesters, specifically those based on oxalic acid. Several different polyester plasticizers can be used, such as a copolyester comprising a polyethylene glycol (PEG) linked to succinate and oxalate units. Thus, the PEG is incorporated by chemical bonds into a polyester by copolymerization.
Recently, cyanoacrylate has been receiving much attention as a drug and gene delivery carrier, and anticancer drug loaded cyanoacrylate nanoparticles have been developed to treat cancer. Most drugs are either physically or chemically immiscible with cyanoacrylates. In the case of hydrophilic drugs, they cannot be miscible physically, and in the case of hydrophobic drugs, they can be miscible, but drugs which contain amine groups readily initiate cyanoacrylate polymerization. It would be desirable to deliver therapeutics to the site to which the adhesive is applied, such as antibiotics to prevent infection of a surgical site or anticancer agents to prevent cancer recurrence after surgery.
U.S. Pat. Nos. 6,746,667 to Badejo, et al., 6,942,875 to Hedgpeth, and 6,767,552 to Narang (all assigned to Closure Medical Co.), disclose haloprogin, an antifungal agent, mixed with 2-octylcyanoacrylate (OCA) monomer by adding haloprogin directly into OCA; and used said agent for different topical applications to remedy infections such as tenia pedis, oral fungal, and skin yeast. Direct mixing of haloprogin with the cyanoacrylate is possible because haloprogin is hydrophobic and does not contain any amine group in the structure that would initiate cyanoacrylate polymerization. Thus, such a system would not work with drugs that are hydrophilic or which have amine groups in their structure.
U.S. Pat. No. 6,086,906 to Greff, et al. (assigned to Medlogic Global Co.) discloses various antimicrobial agents mixed directly with octylcyanoacrylate, but only polyvinylpyrrolidone iodine complex was compatible with the cyanoacrylate and showed a broad spectrum of antibacterial activity. Polyvinylpyrrolidone is a polymer and has a tertiary amine group in its structure, but it is used make a complex with iodine. This tertiary amine cannot initiate cyanoacrylate polymerization.
U.S. Pat. No. 6,974,585 to Askill discloses a cyanoacrylate formulation containing mixed antibiotics (0.3% neomycin, 0.15% polymyxin B, and 0.55% bacitracin zinc). These drugs, however, form a suspension that does not mix with cyanoacrylate monomer homogeneously and they form a suspension. The formulation must be prepared in the operating room on an as-needed basis and used immediately; which is typically not convenient, especially for consumer use.
Therefore, there is a need for a cyanoacrylate adhesive (1) that is readily absorbable in the body; (2) that does not cause significant tissue toxicity; (3) that can transport drug molecules effectively at a site of application for therapeutic treatment; and (4) that is a formulation that is easy to use.